Hindawi Publishing Corporation

Evidence-Based Complementary and Alternative Medicine

Volume 2015, Article ID 975632, 10 pages
http://dx.doi.org/10.1155/2015/975632

Review Article
Mediators, Receptors, and Signalling Pathways in the
Anti-Inflammatory and Antihyperalgesic Effects of Acupuncture

John L. McDonald, Allan W. Cripps, and Peter K. Smith

School of Medicine, Griffith Health Institute, Griffith Health, Griffith University, Southport, QLD 4211, Australia

Correspondence should be addressed to John L. McDonald; twindragon@bigpond.com

Received 11 December 2014; Accepted 30 March 2015

Academic Editor: Xianghong Jing

Copyright © 2015 John L. McDonald et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Acupuncture has been used for millennia to treat allergic diseases including both intermittent rhinitis and persistent rhinitis.
Besides the research on the efficacy and safety of acupuncture treatment for allergic rhinitis, research has also investigated how
acupuncture might modulate immune function to exert anti-inflammatory effects. A proposed model has previously hypothesized
that acupuncture might downregulate proinflammatory neuropeptides, proinflammatory cytokines, and neurotrophins, modu-
lating transient receptor potential vallinoid (TRPV1), a G-protein coupled receptor which plays a central role in allergic rhinitis.
Recent research has been largely supportive of this model. New advances in research include the discovery of a novel cholinergic
anti-inflammatory pathway activated by acupuncture. A chemokine-mediated proliferation of opioid-containing macrophages
in inflamed tissues, in response to acupuncture, has also been demonstrated for the first time. Further research on the complex
cross talk between receptors during inflammation is also helping to elucidate the mediators and signalling pathways activated by
acupuncture.

1. Introduction substance P (SP), calcitonin gene-related peptide (CGRP)

In our previous publication, research on the anti-inflamma-
tory effects of acupuncture was reviewed and a model was
proposed to guide further research [1]. This review included
both demonstrated and proposed effects of acupuncture
and drew from both animal and human studies. Anti-
inflammatory effects of acupuncture in contexts other than
allergic rhinitis were explored for their potential relevance
to allergic rhinitis, especially research involving proinflam-
matory neuropeptides and neurotrophins and modulation of
the transient receptor potential vallinoid 1 (TRPV1), a central
receptor in allergic inflammatory response.
New research has expanded and clarified the under-
standing of inflammatory response and how acupuncture
might modulate it, and hence a revised model for the anti-
inflammatory effects of acupuncture is proposed.
2. The Previously Proposed
Model (2013 Model)
Our 2013 model proposed that, in allergic rhinitis, acu-
puncture downregulated proinflammatory neuropeptides,
and vasoactive intestinal peptide (VIP); downregulated neu-
rotrophins, nerve growth factor (NGF), and brain-derived
neurotrophic factor (BDNF); and downregulated Th2 and
proinflammatory cytokines and possibly upregulated Th1
cytokines, thereby shifting Th1/Th2 balance away from Th2
dominance [1]. Acupuncture-induced modulation of TRPV1
(both demonstrated and hypothesised) was also explored.
3. Effects of Acupuncture on
Inflammatory Oedema
Inflammatory oedema has been significantly reduced by
acupuncture in rodent and murine models of induced hind
paw inflammation [2, 3]. This antioedema effect is mediated
via the HPA axis as various disruptions of the HPA axis
obliterate or significantly attenuate the effect [2, 3]. Many of
the pathways, mediators, and receptors involved in acupunc-
ture attenuation of inflammatory hyperalgesia appear to
have either no effect or delayed effects on inflammatory
oedema [4, 5]. For example, opioid pathways are implicated
in acupuncture effects on inflammatory hyperalgesia but have
2 Evidence-Based Complementary and Alternative Medicine
generally been shown to have no influence on inflamma-
tory oedema as opioid antagonists did not diminish the
antioedema effect [4, 6–8]. One study, however, has shown
slight reduction in inflammatory oedema which was blocked
by opiate antagonists naloxone and natrindole [9].
A single acupuncture treatment was previously reported
to produce a significant but short-lived (less than 15 min-
utes) improvement in the patency of the nasal airway [28].
However, subjective sensations of nasal congestion have
consistently been reported to decrease significantly for much
longer periods following acupuncture for allergic rhinitis in
adults [29–33].
Swelling of the nasal mucosa in allergic rhinitis has been
linked to proinflammatory neuropeptides, proinflammatory
cytokines, neurotrophins, and chemokines [34].
3.1. Neuropeptides. Downregulation of proinflammatory
neuropeptides, SP, and VIP, after EA, has previously been
reported in adults with persistent allergic rhinitis [35]. SP
was also found to decrease sharply (by 83.2%) 18 to 24
hours after the first manual acupuncture treatment in adults
with persistent allergic rhinitis in a study conducted by the
authors (unpublished data). Substance P expression was also
inhibited in the nasal mucosa of mice with experimentally
induced allergic rhinitis following acupuncture (associated
with inhibition of signal transducer and activator of
transcription 6 (STAT 6), nuclear factor kappa B (NF𝜅B),
and inducible nitric oxide synthase (iNOS)) [36]. While
CGRP downregulation after acupuncture has been reported
in migraine, menopausal hot flushes, and spinal nerve lesion
studies, to date no studies have shown a downregulation of
CGRP in allergic rhinitis.
3.2. Cytokines. STAT 6 and NF𝜅B are transcription factors
which play an essential role in Th2 cell differentiation [36].
Inhibition of STAT 6 and NF𝜅B would therefore suppress Th2
cell differentiation, shifting the Th1/Th2 balance away from
Th2 dominance, which characterizes atopy [36]. Significant
decreases in STAT 6 and NF𝜅B, along with the vasodilator
iNOS were reported in the mouse study mentioned in the
previous paragraph [36]. A recent human study comparing
acupuncture with Loratadine for perennial allergic rhinitis
reported an increase in mean values for interleukin-10 (IL-
10), but the increase was not statistically significant, possibly
due the study being underpowered [37]. The same study
also found no change in allergen-specific immunoglobulin E
(IgE) for house dust mite, total IgE, interleukin-4 (IL-4), or
interferon gamma (IFN-𝛾) [37]. A small number of earlier
human studies on the treatment of allergic rhinitis with
acupuncture showed that a trend towards Th2 cytokines os
being downregulated, but very little evidence of Th1 cytokines
is being upregulated [31, 38–40].
3.3. Neurotrophins. Neurotrophins have been shown to be
selectively upregulated or downregulated by acupuncture
depending on the condition. Recent research on neu-
rotrophins has mainly focused on cerebral ischaemia, spinal
cord injury, and depression [13, 41–44]. No research has yet
been published on the possible modulation of neurotrophins
by acupuncture in allergic rhinitis. It is hypothesised, how-
ever, that the abundance of VIP+ parasympathetic nerves
around blood vessels in the lamina propria of the nasal
mucosa (which has been observed in allergic rhinitis) may be
the result of upregulation of neurotrophins, and this neuronal
abundance would contribute to exacerbating inflammatory
oedema in the nasal mucosa [45–47].
3.4. Chemokines. Chemokines have received little attention
from acupuncture researchers until very recently. A new
study has reported that EA upregulated chemokine CXCL10
in a rodent model of complete Freund’s adjuvant- (CFA-)
induced hind paw inflammation [16]. EA increased the
production and release of both IFN-𝛾 and CXCL10 which
in turn increased the number of infiltrating opioid peptide-
containing CXCR3+ macrophages [16]. This study establishes
an important novel link between immune system mediators
such as cytokines, chemokines, and macrophages and the
nervous system’s opioid pathways.
The effects of acupuncture on chemokines and chemok-
ine receptors appear to be selective. The upregulation of
CXCL10 increased the production and release of CXCR3+
macrophages which contain opioids [16]. Activation of opi-
oid receptors, in turn, will desensitize chemokine receptors
thereby inhibiting the production and release of proinflam-
matory cytokines as well as the chemokines CCL2, CCL3,
and CXCL8 [48]. In a rat model of embryo implantation
failure, acupuncture increased expression of CCL2, CXCL8,
and the subset of uterine natural killer (uNK) cells in the
endometrium and reduced embryo implantation failure [49].
4. Complex Cross Talk between Receptors
Chemokine receptors, opioid receptors and TRPV1 receptors
have been reported to participate in complex cross talk,
not unlike that between neuropeptides, cytokines, and neu-
rotrophins [48] Chemokine receptors and opioid receptors
can inhibit each other by a process known as heterologous
desensitization [48]. Adenosine, by activating A2a receptors,
can also desensitize chemokine receptors [48] (see Figure 1).
Chemokine receptors sensitize TRPV1; hence, any desen-
sitization of chemokine receptors (by adenosine or opioid
receptors) would inhibit the sensitization of TRPV1 (via a
phospholipase C 𝛽/protein kinase C [PLC𝛽/PKC] pathway)
[48]. Interactions between cannabinoid receptors and opioid
receptors after acupuncture have been reported. Cannabinoid
receptor CB2 has been shown to participate in the EA-
induced increase of opioid expression in keratinocytes in
inflamed skin (in a CFA rat hind paw inflammation model)
[12].
Cannabinoid receptor CB1 has been shown to medi-
ate phosphorylation of both STAT3 and glycogen synthase
kinase-3𝛽 after acupuncture in rodent cerebral ischaemia
studies [50, 51].
Upregulation of CB1 expression after EA also produced
upregulation of dopamine receptors D1 and D2 in the
striatum (in a CFA rat hind paw inflammation model) [14].
Since acupuncture has already been shown to be capable
of activating adenosine and opioid receptors and now has
Evidence-Based Complementary and Alternative Medicine
been shown to selectively modulate chemokines, there are
a number of possible pathways via which TRPV1 might be
downregulated by acupuncture.
EA has previously been reported to downregulate TRPV1
by inhibiting phosphorylation of PI3K in the dorsal horn of
rats (in a carrageenan hind paw inflammation model) [19].
NGF activates the tyrosine kinase A/phosphatidylinositol 3-
kinase/phosphatidylinositol phosphate 3/protein kinase Akt
(trkA/PI3K/PIP3/Akt) signalling pathway which increases
the sensitivity and expression of TRPV1, so blocking this
pathway would prevent this sensitization of TRPV1 by
NGF [19]. EA also activated p38 mitogen activated protein
kinase/activating transcription factor 2/transient receptor
potential vallinoid (p38 MAPK/ATF-2/TRPV1) signalling
pathway thereby downregulating TRPV1 expression in the
dorsal horn of rats; however, cyclooxygenase 2 (COX-2) was
found to play no role (in a CFA hind paw inflammation
model) [5]. In the same study, hind paw oedema was
unchanged until day 14 after CFA injection. However, the
reasons for this delayed action are unclear [5].
5. Effects of Acupuncture on Thermal
Hyperalgesia and Mechanical Allodynia in
Inflammatory and Neuropathic Pain
According to the ancient Roman doctor Celsius, inflam-
mation was characterised by redness, heat, swelling, and
pain [52]. In research using animal inflammatory pain mod-
els, pain threshold is generally measured as a response to
mechanical pressure (allodynia) or to changes in tempera-
ture, usually heat (thermal hyperalgesia). In reducing inflam-
matory hyperalgesia, low frequency EA (typically 1 to 4 Hz)
has been consistently reported to be effective (see Table 1).
However, there is conflicting data on the effectiveness of high
frequency EA (100–150 Hz) with some researchers reporting
that 120 Hz EA failed to alleviate thermal hyperalgesia and
mechanical allodynia in diabetic neuropathic pain in rats,
while 2 Hz EA was effective [22]. Other studies have reported
effective attenuation of inflammatory hind paw hyperalgesia
in rats using 100 Hz EA [11, 14, 16].
Low frequency EA (2 Hz) effectively relieved mechanical
allodynia in a rat spinal nerve ligation model [23]. This
improvement in allodynia was associated with a reduction
of both TRPV1 and CGRP in the ipsilateral spinal dorsal
horn immediately above and below the lesioned level (L5)
[23]. Since TRPV1 is capable of producing and releasing
both CGRP and SP, the decrease in CGRP may be a direct
result of the reduced expression of TRPV1 [53]. Additionally,
since CGRP and SP interpromote each other, the CGRP
downregulation could be secondary to a downregulation of
SP production and release by TRPV1 [54].
EA effects on thermal hyperalgesia were blunted, but not
obliterated, in TRPV1 knock-out mice [55]. TRPV1 knock-
out mice required a stronger EA stimulation than wild type (C
57 BL/6) mice to achieve an analgesic effect [55]. This suggests
that while TRPV1 downregulation contributes to EA effects
on thermal hyperalgesia, TRPV1 is not solely responsible, as
TRPV1 knock-out did not obliterate the effect. In contrast,
3
histamine-induced itch is completely extinguished in TRPV1
knock-out mice [56].
Low frequency EA (2 Hz) has also been shown to decrease
mechanical hyperalgesia in both CFA and carrageenan-
induced CD1 mouse hind paw inflammation, accompanied
by a significant downregulation of acid sensing ion channel
3 (ASIC3) overexpression in dorsal root ganglion neurons
[17]. In another study, also using CFA and carrageenan-
induced mouse hind paw inflammation (this time in ICR
mice), 2 Hz EA reduced mechanical and thermal hyperalgesia
accompanied with decreased expression of sodium voltage-
gated (Nav) channels Nav1.7 and Nav1.8 (but not Nav1.9) in
dorsal root ganglion neurons [18].
In another CFA hind paw inflammation study with rats,
EA alternating between 2 Hz and 100 Hz alleviated mechan-
ical allodynia and blocked activation of the extracellular-
regulated protein kinase 1/2-cyclooxygenase-2 (ERK1/2-
COX-2) and extracellular-regulated protein kinase 1/2-cAMP
response element binding protein- neurokinin-1 receptor
(ERK1/2-CREB-NK-1) pathways, but had no effect on Ets-like
kinase 1 (Elk1) (a downstream nuclear substrate of ERK1/2)
in the spinal dorsal horn [15]. Since SP is the endogenous
ligand for NK-1 receptor, blocking NK-1 would downregulate
the proinflammatory effects of SP, as has been previously
reported [57].
In a spinal cord injury neuropathic pain model in rats,
manual acupuncture significantly relieved thermal hyper-
algesia and mechanical allodynia [24]. These acupuncture
analgesic effects were associated with Jun-N-terminal kinase
(JNK) inhibition in astrocytes in lamina I-II of the dorsal
horn and inhibited phosphorylation of JNK downstream
substrate, c-Jun [24]. Acupuncture also inhibited JNK-
dependent expression of chemokines monocyte chemotac-
tic protein 1 (MCP-1) (also known as CCL2), macrophage
inflammatory protein 1𝛽 (MIP-1𝛽) (also known as CCL4),
and macrophage inflammatory protein 3𝛼 (MIP-3𝛼) (also
known as CCL20) in spinal astrocytes [24]. In a rat CFA hind
paw study, EA alleviated mechanical allodynia (alternating
between 2 Hz and 100 Hz) but not paw oedema by suppress-
ing the spinal JNK1/2 pathway [4]. In this study, TRPV1
expression in the spinal dorsal horn was unaffected [4].
Further research is needed to investigate whether these
modulations of TRPV1, produced by acupuncture in the
spinal dorsal horn of rats or mice, can also be found in the
trigeminal ganglia or nasal mucosa of humans with allergic
rhinitis.
6. A Novel Cholinergic
Anti-Inflammatory Pathway
It has been suggested that acupuncture may activate a cholin-
ergic anti-inflammatory pathway involving acetylcholine
release from vagus nerves binding to 𝛼7-nicotinic receptors
(𝛼7-nAChRs) on macrophages, thereby inhibiting the release
of proinflammatory cytokines [58]. A recent study by Torres-
Rosas et al. has demonstrated that there is in fact an anti-
inflammatory pathway activated by EA which involves the
vagus and sciatic nerves and is mediated by dopamine [59].
 Table 1: Effects of electroacupuncture and manual acupuncture on inflammatory signalling pathways and receptors. 4
Acupuncture Thermal Mechanical
Author and year Model EA/acup Effect Oedema
points hyperalgesia allodynia
Huang et al. CFA hind paw
EA 100 Hz (B) ST 36, SP 6 No effect Reduced
2004 [10] FSD rats
Reduced thermal hyperalgesia and increased EA tolerance
Huang et al. CFA hind paw
EA 100 Hz (B) ST 36, SP 6 EA effects abolished by high dose Naloxone suggesting Reduced
2008 [11] FSD rats
dynorphin mediation
Su et al. CFA hind paw
EA 2 Hz (I) GB 30, GB 34 macrophages, and T-lymphocytes in inflamed skin via Reduced Reduced
2011 [12] MSD rats
activation of CB2 cannabinoid receptors
Increased POMC and 𝛽-END expression in keratinocytes,

Zhang et al. CFA hind paw

EA 10 Hz GB 30 Suppressed spinal IL-17 and p-NR1 Reduced Reduced
2012 [13] rats
Shou et al. CFA hind paw EA 2 Hz Increased CB1 expression with upregulation of D1 and D2
ST 36, BL 60 Reduced
2013 [14] MSD rats EA 100 Hz expression in striatum
Fang et al. CFA hind paw Inhibition of p38/MAPK/ATF-2/TRPV1 pathway producing Reduced
EA 2/100 Hz alt (B) ST 36, BL 60 Reduced
2013 [5] MSD rats downregulation of TRPV1 in spinal dorsal horn only at day 14
Fang et al. CFA hind paw Inhibited ERK1/2-COX-2 and ERK1/2-CREB-NK-1 pathway
EA 2/100 Hz alt (B) ST 36, BL 60 Reduced
2014 [15] MSD rats Downregulated NK-1 hence inhibiting SP
Wang et al. CFA hind paw EA effects suppressed by opiate antagonists naloxone and Reduced
EA 100 Hz (B) GB 30 Reduced Reduced
2013 [9] M Wistar rats natrindole slightly
TNF-𝛼 and IL-1𝛽 downregulated,
Wang et al. CFA hind paw IL-13 upregulated, and IL-1𝛼 and IL-4 unchanged
EA 100 Hz (B) GB 30 Reduced Reduced
2014 [16] M Wistar rats IFN-𝛾 up-regulated stimulating CXCL10 increasing CXCR3+
macrophages
Du et al. CFA hind paw
EA 2/100 Hz alt (B) ST 36, BL 60 Inhibited JNK1/2 and COX-2 but not TRPV1 Reduced No effect
2014 [4] MSD rats
Carrageenan &
Chen et al.
CFA hind paw EA 2 Hz ST 36 Decreased overexpression of ASIC3 in DRG Reduced
2011 [17]
CDI mice
Carrageenan &
Huang et al. Decreased expression of sodium voltage-gated channels Nav 1.7
CFA hind paw F EA 2 Hz ST 36 Reduced Reduced
2013 [18] and Nav 1.8 but not Nav 1.9 in DRG
ICR mice
Carrageenan
Kim et al.
hind paw MSD EA 2/100 Hz alt (B) ST 36, SP 6 Inhibition of p-PI3K blocked trkA/PI3K/PIP3/Akt pathway Reduced Reduced
2012 [19]
rats
Carrageenan Increased IL-10 in inflamed muscle
da Silva et al.
gastrocnemius Manual acup SP 6 Induced a phenotypic switch from M1 to M2 macrophages in Reduced Reduced Reduced
2015 [20]
C57BL/6 mice inflamed muscle
(I) SI 3, TE 8
Reduced
Capsaicin hind (GB 30, GB 34; SI 3 & TE 8 effective, but other point combinations were not
Kim et al. secondary but not
paw EA 2 Hz BL 40, BL 60; Secondary (but nor primary) hyperalgesia is mediated by MOR
2009 [21] primary
MSD rats GV 2, GV 6; LI and DOR but not KOR or adrenergic receptors
hyperalgesia
3, LI 6)
Evidence-Based Complementary and Alternative Medicine
 Table 1: Continued.
Acupuncture Thermal Mechanical
Author and year Model EA/acup Effect Oedema
points hyperalgesia allodynia
EA 2 Hz
Exp. diabetic
Hwang et al. EA 2 Hz (B) SP 9 or ST Decreased cleavage of p35 to p25 hence inhibited reduced; EA 2 Hz reduced;
neuropathic
2011 [22] EA 120 Hz 36 p35/p25/Cdk5/MAPK and/or p35/p25/Cdk5/NMDA pathways EA 120 Hz EA 120 Hz no effect
pain MSD rats
no effect
Jiang et al.
SNL MSD rats EA 2 Hz (I) ST 36, BL 60 Downregulated TRPV1 in spinal dorsal horn and reduced CGRP Reduced
2013 [23]
Lee et al. GV 26, (B) GB Inhibited JNK/p-c-Jun in spinal astrocytes
SCI MSD rats Manual acup Reduced Reduced
Evidence-Based Complementary and Alternative Medicine

2013 [24] 34 Decreased chemokines MCP-1, MIP-1𝛽, and MIP-3𝛼

Reduced
Yu et al. EA 2 Hz EA reduced ERK1/2 phosphorlylation and P2X3 expression in Reduced
CCI SD rats ST 36, GB 34
2013 [25] EA 15 Hz spinal cord
15 Hz
Hsu et al. EA 2 Hz EA increased cerebral TRPV4 but not TRPV1 No change in
EA 2 Hz >

CCI MSD rats (R) ST 36, ST 37 Reduced Reduced

EA 2 Hz > 15 Hz

2014 [26] EA 15 Hz spinal TRPV4 or TRPV1

Suppressed lymphocyte proliferation
(B) ST 36,
Wang et al. Surgical trauma Reduced splenic T cells production of Th1 cytokines (IL-2 and
EA 2/60 Hz alt Lanwei Reduced Reduced
2009 [27] MSD rats IFN-𝛾) increased Th2 cytokines (IL-4, IL-10)
(M-LE-13)
Suppressed activity of ERK1/2, p38, NF-𝜅B, and AP-1
EA: electroacupuncture, acup: acupuncture, CFA hind paw: model of inflammation induced by injection of complete Freund’s adjuvant into rats’ hind paws, FSD rats: female Sprague Dawley rats, MSD: male Sprague

phosphorylation of NR1, SP: substance P, CGRP: calcitonin gene-related peptide, NK-1: neurokinin 1 receptor, DRG: dorsal root ganglion, MAPK: mitogen activated protein kinase, ATF-2: activating transcription
factor 2, ERK: extracellular-regulated protein kinase, CREB: cAMP response element binding protein, NK-1: neurokinin 1 receptor, JNK: c-jun N terminal kinase, ASIC3: acid sensing ion channel 3, Nav: sodium
Dawley rats, alt: alternating, (B): bilateral, (I): ipsilateral, CB: cannabinoid receptor, D: dopamine receptor, TRPV: transient receptor potential vallinoid, proopiomelanocortin, 𝛽-END: beta endorphin, p-NR1:

voltage-gated channels, trkA: tyrosine kinase A, PI3K/PIP3: phosphatidylinositol 3 kinase/phosphatidylinositol phosphate 3 pathway, MOR: Mu opioid receptor, DOR: delta opioid receptor, KOR: kappa opioid
receptor, AP-1: activator protein 1, Cdk5: cyclin-dependent kinase 5, and NMDA: N-methyl-D-aspartate.
5
6 Evidence-Based Complementary and Alternative Medicine

Adenosine
Activates NGF
A2a 1 Activates
Increases production
Desensitizes and release
4 trkA
2 CCR2 MOR MEK
CCR3 Desensitizes DOR 5
CXCR8 KOR
PLC𝛽 PI3K
PIP3 Inhibits
PKC
SP
Sensitizes
Early phase response: 3
Sneezing TRPV1 CGRP
Nasal itching Increases production
Activates and release
Act synergistically to
PLA2 promote degranulation
LO

H1R Histamine Mast cell

Sensitizes Inhibits
Desensitizes Increases production and release
Activates

Figure 1: Proposed model for the complex cross talk between various receptors and mediators in early phase response in allergic rhinitis.
1: nerve growth factor (NGF) activates tyrosine kinase A (TrkA) receptor which in turn increases production and release of substance P
(SP). Activation of TrkA receptor also initiates signalling via the PI3K/PIP3 pathway to increase expression and sensitivity of transient
receptor potential vallinoid (TRPV1) receptor. 2: chemokine receptors (CCR2, CCR3, and CXCR8) sensitize TRPV1 receptor via a PLC𝛽/PKC
pathway. 3: TRPV1 receptor increases production and release of proinflammatory neuropeptides SP and CGRP which act synergistically to
promote degranulation of primed mast cells. Histamine released by mast cells activates histamine 1 receptor (H1R) producing signalling
via the phospholipase A2 /lipoxygenase pathway to activate TRPV1, triggering early phase allergic inflammatory response. 4: chemokine
receptors are heterologously desensitized by both adenosine (A2a) receptors and opioid receptors (MOR, DOR, and KOR). 5: Substance P
is inhibited by met-enkephalin via Mu opioid receptors (MOR). A2a: adenosine 2a receptor, CCR2, CCR3: CC chemokine receptors 2 & 3,
CXCR8: CXC chemokine receptor 8, PLC𝛽: phospholipase C 𝛽, PKC: protein kinase C, NGF: nerve growth factor, TRPV1: transient receptor
potential vallinoid 1, TrkA: tyrosine kinase A receptor, H1R: histamine 1 receptor, SP: substance P, CGRP: calcitonin gene-related peptide,
PI3K/PIP3: phosphatidylinositol 3 kinase/phosphatidylinositol phosphate 3 pathway, PLA2 /LO: phospholipase A2 /lipoxygenase pathway,
MOR: Mu opioid receptor, DOR: delta opioid receptor, KOR: kappa opioid receptor, and MEK: met-enkephalin.

However, this study also found that 𝛼7-nAChRs were not
involved in this anti-inflammatory pathway [59]. In a mouse
model of induced sepsis, EA rescued mice from polymicro-
bial peritonitis and controlled systemic inflammation [59].
EA stimulation of the sciatic nerve induced release of DOPA
decarboxylase from the vagus nerve leading to dopamine
production in the adrenal medulla [59]. Of the dopamine
receptor family, D1 receptors were shown to be essential to EA
anti-inflammatory effects, but D2 receptors appeared to have
little involvement [59]. Vagal stimulation was also associated
with reduced serum levels of the cytokines tumour necrosis
factor (TNF), MCP-1/CCL2, IL-6, and IFN-𝛾 [59]. TRPV1
agonist, capsaicin, abolished the anti-inflammatory effects of
EA [59]. This underlines the importance of TRPV1 role in the
anti-inflammatory effects of acupuncture.
7. Adenosine
Adenosine triphosphate (ATP) released locally at acupunc-
ture points, in response to needle stimulation is metabolized
into adenosine, which activates adenosine A1 receptors,
creating an analgesic effect in inflammatory pain [60, 61].
Adenosine, via A2a receptors, has also been shown to desen-
sitize chemokine receptors, hence blocking the capacity of
chemokine receptors to both sensitize TRPV1 receptors via
a PLC𝛽/PKC pathway and to desensitize opioid receptors
[48]. Adenosine has previously been reported to inhibit
TRPV1 activation, and this action may be mediated via the
PLC𝛽/PKC pathway [62]. In addition, adenosine, via A3
receptor activation has recently been shown to be effective
in relieving persistent neuropathic pain [63]. Further inves-
tigation is needed to determine whether or not adenosine
modulates TRPV1 (and possibly opioid receptors) in the nasal
mucosa or trigeminal ganglia.
8. A Revised Model for the Effects of
Acupuncture in Allergic Rhinitis
The central importance of TRPV1 in allergic rhinitis raises
the question of how acupuncture might modulate TRPV1
Evidence-Based Complementary and Alternative Medicine 7

Adenosine
Rs

Chemokine
Opioid Rs
Rs

TRPV1

Neurotrophin Cannabinoid
Rs * Rs

Dopamine
Rs

Desensitizes Rs: receptors, TRPV1-: transient receptor

potential vallinoid 1
Sensitizes
∗
Activates There is no direct experimental evidence for this
mutual desensitization. It is suggested on the basis
that a TRPV1 agonist blocked dopamine-mediated
anti-inflammatory effects of acupuncture.

Figure 2: Receptor interactions potentially involved in the anti-inflammatory effects of acupuncture.

either directly or indirectly. In our previous proposed model,
it was suggested that acupuncture might modulate TRPV1 by
blocking neurotrophic sensitization (by blocking phospho-
rylation of PI3K, as seen in EA for neuropathic pain), by
downregulating SP and CGRP (with consequent suppression
of degranulation of primed mast cells) and possibly through
some pathway associated with adenosine. It now appears that
this adenosine-induced downregulation of TRPV1 may occur
through desensitization of chemokines receptors (which sen-
sitize TRPV1 via a PLC𝛽/PKC pathway) [48] (see Figure 1).
Downregulation of SP by met-enkephalin has previously
been reported [64, 65]. New research showing that acupunc-
ture can stimulate production of CXCR3+ macrophages
(which contain met-enkephalin) clarifies the source of
the opioid stimulation. Opioid receptor desensitization of
chemokine receptors, with consequent inhibition of both
cytokine production and sensitization of TRPV1, provides
another pathway via which acupuncture-induced opioid
stimulation could generate anti-inflammatory effects.
TRPV1 interactions with both cannabinoid and dopam-
ine receptors have also now been demonstrated in murine
and rodent studies of inflammatory hyperalgesia (see Table 1).
Further studies are needed to determine whether these effects
of acupuncture in the spinal dorsal root ganglia during
inflammatory hyperalgesia are relevant to the trigeminal
ganglia in allergic rhinitis.
Recent research into the effects of acupuncture on sig-
nalling pathways and receptors in inflammatory pain has
focused mainly on mechanical allodynia and thermal hyper-
algesia, but little new work has been done on inflammatory
oedema. Since TRPV1 appears to play a central role in
inflammatory oedema, it is possible that signalling pathways
activated by acupuncture which are independent of TRPV1
may be associated with reduction of thermal and mechanical
hyperalgesia but not inflammatory oedema [66]. Since nasal
swelling is more significant clinically in allergic rhinitis than
hyperalgesia, signalling pathways identified in hyperalgesia
studies which do not involve TRPV1 may be less relevant to
acupuncture’s effects on allergic rhinitis.
The effects of acupuncture on chemokines and chemok-
ine receptors appear to be selective. While desensitization
of chemokine receptors by adenosine and by interaction
with opioid receptors may reduce sensitivity of TRPV1, it is
also clear that acupuncture can increase chemokines such as
CXCL10, CCL2, and CXCL8.
Interactions between receptor types are now being
reported with an increasing frequency. Acupuncture has
been shown to influence the interactions between opioid
receptors and chemokine receptors, as well as cannabinoid
receptors (see Figure 2). Interactions between cannabinoid
receptors and dopamine receptors have also been shown to
be modulated by acupuncture [14].
9. Conclusion
Our 2013 model proposed that acupuncture downregulates
proinflammatory neuropeptides and neurotrophins, alters
Th1/Th2 cytokine balance, and modulates TRPV1.
Acupuncture has already been shown to downregulate
SP and VIP in allergic rhinitis and may also downregulate
8 Evidence-Based Complementary and Alternative Medicine
CGRP. This reduction in SP and VIP has been associated with
improvements in clinical signs and symptoms.
Acupuncture may downregulate neurotrophins NGF and
BDNF in allergic rhinitis, but evidence is currently lacking.
Acupuncture has been shown to alter Th1/Th2 cytokine
balance away from Th2 dominance in a variety of clinical
contexts including allergic rhinitis; however, more robust
evidence is still needed. The role of transcription factors
involved in Th2 differentiation (such as STAT 6 and NF𝜅B)
merits further investigation.
While numerous new signalling pathways have been
identified in the anti-inflammatory actions of acupuncture
in animal model studies on induced hind paw inflammation,
spinal cord injury, and chronic constriction injury, it is
unclear how much relevance these studies might have to
allergic rhinitis (see Table 1). Frequently, the main outcome
measures for these studies have been measures of inflamma-
tory pain, thermal and mechanical hyperalgesia, as opposed
to inflammatory oedema, which would be more likely to be
relevant to allergic rhinitis.
Recent research has also shown that acupuncture
can modulate chemokines and that interactions between
chemokine and opioid receptors may have relevance to reduc-
ing the expression and sensitivity of TRPV1. Further research
on the effects of acupuncture on chemokines is needed.
A novel cholinergic anti-inflammatory pathway involving
vagal stimulation and dopamine mediation has now been
demonstrated [59]. This pathway is neither parasympathetic
nor sympathetic but involves both. In acupuncture analgesia
research, dopamine receptors have been shown to act in
a selective manner. D1 receptors in the brain inhibited
acupuncture analgesia, while D2 receptors in the spine
enhanced analgesic effects [27]. Torres-Rosas et al. demon-
strated that D1 receptors appeared to play a significant role
in the anti-inflammatory effects of acupuncture while D2
receptors did not [59]. The role of dopamine receptors and
their interactions with cannabinoid receptors, and possibly
TRPV1, in the anti-inflammatory effects of acupuncture
have only just begun to be explored. Further exploration
of receptor interactions and their possible involvement in
acupuncture effects would be valuable.
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
References
[1] J. L. McDonald, A. W. Cripps, P. K. Smith, C. A. Smith, C.
C. Xue, and B. Golianu, “The anti-inflammatory effects of
acupuncture and their relevance to allergic rhinitis: a narrative
review and proposed model,” Evidence-Based Complementary
and Alternative Medicine, vol. 2013, Article ID 591796, 12 pages,
2013.
[2] A. Li, L. Lao, Y. Wang et al., “Electroacupuncture activates
corticotrophin-releasing hormone-containing neurons in the
paraventricular nucleus of the hypothalammus to alleviate
edema in a rat model of inflammation,” BMC Complementary
and Alternative Medicine, vol. 8, article 20, 2008.
[3] A. Li, R.-X. Zhang, Y. Wang et al., “Corticosterone mediates
electroacupuncture-produced anti-edema in a rat model of
inflammation,” BMC Complementary and Alternative Medicine,
vol. 7, article 27, 2007.
[4] J.-Y. Du, J.-Q. Fang, Y. Liang, and J.-F. Fang, “Electroacupunc-
ture attenuates mechanical allodynia by suppressing the spinal
JNK1/2 pathway in a rat model of inflammatory pain,” Brain
Research Bulletin, vol. 108, pp. 27–36, 2014.
[5] J.-Q. Fang, J.-Y. Du, Y. Liang, and J.-F. Fang, “Intervention of
electroacupuncture on spinal p38 MAPK/ATF-2/VR-1 pathway
in treating inflammatory pain induced by CFA in rats,” Molecu-
lar Pain, vol. 9, no. 1, article 13, 2013.
[6] H.-W. Kim, D.-H. Roh, S.-Y. Yoon et al., “The anti-inflammatory
effects of low- and high-frequency electroacupuncture are
mediated by peripheral opioids in a mouse air pouch inflam-
mation model,” Journal of Alternative and Complementary
Medicine, vol. 12, no. 1, pp. 39–44, 2006.
[7] R. Sekido, K. Ishimaru, and M. Sakita, “Differences of
electroacupuncture-induced analgesic effect in normal and
inflammatory conditions in rats,” American Journal of Chinese
Medicine, vol. 31, no. 6, pp. 955–965, 2003.
[8] S. P. Zhang, J. S. Zhang, K. K. L. Yung, and H. Q. Zhang, “Non-
opioid-dependent anti-inflammatory effects of low frequency
electroacupuncture,” Brain Research Bulletin, vol. 62, no. 4, pp.
327–334, 2004.
[9] Y. Wang, D. Hackel, F. Peng, and H. L. Rittner, “Long-term
antinociception by electroacupuncture is mediated via periph-
eral opioid receptors in free-moving rats with inflammatory
hyperalgesia,” European Journal of Pain, vol. 17, no. 10, pp. 1447–
1457, 2013.
[10] C. Huang, Z.-P. Hu, H. Long, Y.-S. Shi, J.-S. Han, and Y.
Wan, “Attenuation of mechanical but not thermal hyperalgesia
by electroacupuncture with the involvement of opioids in rat
model of chronic inflammatory pain,” Brain Research Bulletin,
vol. 63, no. 2, pp. 99–103, 2004.
[11] C. Huang, Z.-Q. Huang, Z.-P. Hu et al., “Electroacupuncture
effects in a rat model of complete Freund’s adjuvant-induced
inflammatory pain: antinociceptive effects enhanced and toler-
ance development accelerated,” Neurochemical Research, vol. 33,
no. 10, pp. 2107–2111, 2008.
[12] T. F. Su, L. H. Zhang, M. Peng et al., “Cannabinoid CB2 receptors
contribute to upregulation of beta-endorphin in inflamed skin
tissues by electroacupuncture,” Molecular Pain, vol. 7, article 98,
2011.
[13] X.-F. Zhang, Y. Zou, Y. Zhao, T.-H. Wang, and W. Zhang,
“Effects of eiectroacupuncture of ‘governor vessel’ acupoints on
changes of BDNF in the cortical motor area of mice with spinal
cord transection,” Journal of Sichuan University, vol. 43, no. 2,
pp. 250–253, 2012.
[14] Y. Shou, Y. Yang, M.-S. Xu, Y.-Q. Zhao, L.-B. Ge, and B.-M.
Zhang, “Electroacupuncture inhibition of hyperalgesia in rats
with adjuvant arthritis: involvement of cannabinoid receptor 1
and dopamine receptor subtypes in striatum,” Evidence-Based
Complementary and Alternative Medicine, vol. 2013, Article ID
393460, 10 pages, 2013.
[15] J. Q. Fang, J. F. Fang, Y. Liang, and J. Y. Du, “Electroacupuncture
mediates extracellular signal-regulated kinase 1/2 pathways
in the spinal cord of rats with inflammatory pain,” BMC
Complementary & Alternative Medicine, vol. 14, no. 1, article 285,
2014.
Evidence-Based Complementary and Alternative Medicine
[16] Y. Wang, R. Gehringer, S. A. Mousa, D. Hackel, A. Brack, and
H. L. Rittner, “CXCL10 controls inflammatory pain via opioid
peptide-containing macrophages in electroacupuncture,” PLoS
ONE, vol. 9, no. 4, Article ID e94696, 2014.
[17] W.-H. Chen, C.-L. Hsieh, C.-P. Huang et al., “Acid-sensing
ion channel 3 mediates peripheral anti-hyperalgesia effects of
acupuncture in mice inflammatory pain,” Journal of Biomedical
Science, vol. 18, no. 1, article 82, 2011.
[18] C.-P. Huang, H.-N. Chen, H.-L. Su et al., “Electroacupuncture
reduces carrageenan- and CFA-induced inflammatory pain
accompanied by changing the expression of Nav1.7 and Nav1.8,
rather than Nav1.9, in mice dorsal root ganglia,” Evidence-Based
Complementary and Alternative Medicine, vol. 2013, Article ID
312184, 8 pages, 2013.
[19] H. N. Kim, Y. R. Kim, J. Y. Jang, H. K. Shin, and B. T.
Choi, “Electroacupuncture inhibits phosphorylation of spinal
phosphatidylinositol 3-kinase/Akt in a carrageenan-induced
inflammatory rat model,” Brain Research Bulletin, vol. 87, no. 2-
3, pp. 199–204, 2012.
[20] M. D. da Silva, F. Bobinski, K. L. Sato, S. J. Kolker, K. A.
Sluka, and A. R. Santos, “IL-10 cytokine released from M2
macrophages is crucial for analgesic and anti-inflammatory
effects of acupuncture in a model of inflammatory muscle pain,”
Molecular Neurobiology, vol. 51, no. 1, pp. 19–31, 2015.
[21] H. Y. Kim, J. Wang, I. Lee, H. K. Kim, K. Chung, and J.
M. Chung, “Electroacupuncture suppresses capsaicin-induced
secondary hyperalgesia through an endogenous spinal opioid
mechanism,” Pain, vol. 145, no. 3, pp. 332–340, 2009.
[22] H. S. Hwang, E. J. Yang, S. M. Lee, S. C. Lee, and S. Choi, “Antial-
lodynic effects of electroacupuncture combined with MK-801
treatment through the regulation of p35/p25 in experimental
diabetic neuropathy,” Experimental Neurobiology, vol. 20, no. 3,
pp. 144–152, 2011.
[23] Y.-L. Jiang, X.-H. Yin, Y.-F. Shen, X.-F. He, and J.-Q. Fang,
“Low frequency electroacupuncture alleviated spinal nerve
ligation induced mechanical allodynia by inhibiting TRPV1
upregulation in ipsilateral undamaged dorsal root ganglia in
rats,” Evidence-Based Complementary and Alternative Medicine,
vol. 2013, Article ID 170910, 9 pages, 2013.
[24] J. Y. Lee, D. C. Choi, T. H. Oh, and T. Y. Yune, “Analgesic effect
of acupuncture is mediated via inhibition of JNK activation in
astrocytes after spinal cord injury,” PLoS ONE, vol. 8, no. 9,
Article ID e73948, 2013.
[25] J. Yu, C. Zhao, and X. Luo, “The effects of electroacupuncture
on the extracellular signal-regulated kinase 1/2/P2X3 signal
pathway in the spinal cord of rats with chronic constriction
injury,” Anesthesia & Analgesia, vol. 116, no. 1, pp. 239–246, 2013.
[26] H.-C. Hsu, N.-Y. Tang, Y.-W. Lin, T.-C. Li, H.-J. Liu, and C.-
L. Hsieh, “Effect of electroacupuncture on rats with chronic
constriction injury-induced neuropathic pain,” The Scientific
World Journal, vol. 2014, Article ID 129875, 9 pages, 2014.
[27] H.-C. Wang, C.-T. Zuo, and Y.-H. Guan, “Research on receptors
related to acupuncture analgesia and positron emission tomog-
raphy radioligands: a review,” Journal of Chinese Integrative
Medicine, vol. 7, no. 6, pp. 575–581, 2009.
[28] Y. C. Park, J. H. Jo, K. E. Hong, W. C. Kang, and S. M. Choi,
“Effect of acupuncture on nasal obstruction in patients with
persistent allergic rhinitis: a randomized, controlled trial,” The
Journal of Korean Acupuncture & Moxibustion Society, vol. 22,
pp. 229–239, 2005.
9
[29] B. Brinkhaus, M. Ortiz, C. M. Witt et al., “Acupuncture in
patients with seasonal allergic rhinitis: a randomized trial,”
Annals of Internal Medicine, vol. 158, no. 4, pp. 225–234, 2013.
[30] S. M. Choi, J. E. Park, S.-S. Li et al., “A multicenter, randomized,
controlled trial testing the effects of acupuncture on allergic
rhinitis,” Allergy, vol. 68, no. 3, pp. 365–374, 2013.
[31] Y. Q. Rao and N. Y. Han, “Therapeutic effect of acupuncture
on allergic rhinitis and its effects on immunologic function,”
Zhongguo Zhen Jiu, vol. 26, pp. 557–560, 2006.
[32] C. C. Xue, X. An, T. P. Cheung et al., “Acupuncture for persistent
allergic rhinitis: a randomised, sham-controlled trial,” Medical
Journal of Australia, vol. 187, no. 6, pp. 337–341, 2007.
[33] C. C. Xue, R. English, J. J. Zhang, C. da Costa, and C. G. Li,
“Effect of acupuncture in the treatment of seasonal allergic
rhinitis: a randomized controlled clinical trial,” The American
Journal of Chinese Medicine, vol. 30, no. 1, pp. 1–11, 2002.
[34] S. Sarin, B. Undem, A. Sanico, and A. Togias, “The role of the
nervous system in rhinitis,” The Journal of Allergy and Clinical
Immunology, vol. 118, no. 5, pp. 999–1014, 2006.
[35] Y.-M. Li, L.-X. Zhuang, X.-S. Lai, and G.-H. Jiang, “Effects of
electroacupuncture on plasma vasoactive intestinal peptide and
substance P in perennial allergic rhinitis patients,” Zhen Ci Yan
Jiu, vol. 32, no. 2, pp. 136–138, 2007.
[36] D. Jung, S. Lee, and S. Hong, “Effects of acupuncture and moxi-
bustion in a mouse model of allergic rhinitis,” Otolaryngology—
Head and Neck Surgery, vol. 146, no. 1, pp. 19–25, 2012.
[37] B. Hauswald, C. Dill, J. Boxberger, E. Kuhlisch, T. Zahnert, and
Y. M. Yarin, “The effectiveness of acupuncture compared to
loratadine in patients allergic to house dust mites,” Journal of
Allergy, vol. 2014, Article ID 654632, 7 pages, 2014.
[38] F. B. Petti, A. Liguori, and F. Ippoliti, “Study on cytokines IL-2,
IL-6, IL-10 in patients of chronic allergic rhinitis treated with
acupuncture,” Journal of Traditional Chinese Medicine, vol. 22,
no. 2, pp. 104–111, 2002.
[39] H.-S. Shiue, Y.-S. Lee, C.-N. Tsai, Y.-M. Hsueh, J.-R. Sheu,
and H.-H. Chang, “DNA microarray analysis of the effect on
inflammation in patients treated with acupuncture for allergic
rhinitis,” Journal of Alternative and Complementary Medicine,
vol. 14, no. 6, pp. 689–698, 2008.
[40] M.-F. Zheng, C. Lin, L.-P. Zheng, and F.-R. He, “Effects of
acupuncture-moxibustion on monocyte Th1/Th2 cytokine in
peripheral blood of patients with perennial allergic rhinitis,”
Journal of Acupuncture and Tuina Science, vol. 8, no. 2, pp. 85–
88, 2010.
[41] Y. R. Kim, H. N. Kim, S. M. Ahn, Y. H. Choi, H. K. Shin, and B.
T. Choi, “Electroacupuncture promotes post-stroke functional
recovery via enhancing endogenous neurogenesis in mouse
focal cerebral ischemia,” PLoS ONE, vol. 9, no. 2, Article ID
e90000, 2014.
[42] J. Liang, J. Lu, S. F. Cui, J. R. Wang, and Y. Tu, “Effect
of acupuncture on expression of brain-derived neurotrophic
factor gene and protein in frontal cortex and hippocampus of
depression rats,” Zhen Ci Yan Jiu, vol. 37, no. 1, pp. 20–24, 2012.
[43] D. Lin, I. D. L. Pena, L. Lin, S.-F. Zhou, C. V. Borlongan, and C.
Cao, “The neuroprotective role of acupuncture and activation
of the BDNF signaling pathway,” International Journal of Molec-
ular Sciences, vol. 15, no. 2, pp. 3234–3252, 2014.
[44] H. Sun, H. Zhao, C. Ma et al., “Effects of electroacupuncture
on depression and the production of glial cell line-derived
neurotrophic factor compared with fluoxetine: a randomized
controlled pilot study,” Journal of Alternative and Complemen-
tary Medicine, vol. 19, no. 9, pp. 733–739, 2013.
10 Evidence-Based Complementary and Alternative Medicine

[45] S. Y. Fang and C. L. Shen, “Neuropeptide innervation and neu- [62] M. Tominaga and T. Tominaga, “Structure and function of
roendocrine cells in allergic rhinitis and chronic hypertrophic TRPV1,” Pflugers Archiv, vol. 451, no. 1, pp. 143–150, 2005.
rhinitis,” Clinical and Experimental Allergy, vol. 28, no. 2, pp. [63] J. W. Little, A. Ford, A. M. Symons-Liguori et al., “Endogenous
228–232, 1998. adenosine A3 receptor activation selectively alleviates persistent
[46] J. M. Figueroa, E. Mansilla, and A. M. Suburo, “Innervation pain states,” Brain, vol. 138, no. 1, pp. 28–35, 2015.
of nasal turbinate blood vessels in rhinitic and nonrhinitic [64] M. K. Ai, X. M. Guan, C. G. Zhu, and L. L. Vacca, “The
children,” American Journal of Respiratory and Critical Care influence of electroacupuncture and morphine on Substance P
Medicine, vol. 157, no. 6, pp. 1959–1966, 1998. (SP) Enkephalin (ENK) and Acetylcholine Esterase (AChE) in
[47] A. Fischer, A. Wussow, A. Cryer et al., “Neuronal plasticity in the spinal cord of rats,” Zhen Ci Yan Jiu, vol. 11, pp. 96–105, 1986.
persistent perennial allergic rhinitis,” Journal of Occupational [65] I. Kondo, J. C. G. Marvizon, B. B. Song et al., “Inhibition by
and Environmental Medicine, vol. 47, no. 1, pp. 20–25, 2005. spinal 𝜇- and 𝛿-opioid agonists of afferent-evoked substance P
[48] N. Zhang and J. J. Oppenheim, “Crosstalk between chemokines release,” The Journal of Neuroscience, vol. 25, no. 14, pp. 3651–
and neuronal receptors bridges immune and nervous systems,” 3660, 2005.
Journal of Leukocyte Biology, vol. 78, no. 6, pp. 1210–1214, 2005. [66] J. Keeble, F. Russell, B. Curtis, A. Starr, E. Pinter, and S. D. Brain,
[49] W. Gao, X. Tang, Z. Chen et al., “Effects of acupuncture on CCL2 “Involvement of transient receptor potential vanilloid 1 in the
and CXCL8 expression and the subset of uNK cells in rats with vascular and hyperalgesic components of joint inflammation,”
embryo implantation failure,” Evidence-Based Complementary Arthritis & Rheumatism, vol. 52, no. 10, pp. 3248–3256, 2005.
and Alternative Medicine, vol. 2013, Article ID 678390, 12 pages,
2013.
[50] H. Wei, X. Yao, L. Yang et al., “Glycogen synthase kinase-3𝛽 is
involved in electroacupuncture pretreatment via the cannabi-
noid CB1 receptor in ischemic stroke,” Molecular Neurobiology,
vol. 49, no. 1, pp. 326–336, 2014.
[51] H. Zhou, Z. Zhang, H. Wei et al., “Activation of STAT3 is
involved in neuroprotection by electroacupuncture pretreat-
ment via cannabinoid CB1 receptors in rats,” Brain Research, vol.
1529, pp. 154–164, 2013.
[52] M. Rocha e Silva, “A brief survey of the history of inflammation.
1978,” Agents and Actions, vol. 43, no. 3-4, pp. 86–90, 1994.
[53] Q. T. Dinh, D. A. Groneberg, C. Peiser et al., “Substance P
expression in TRPV1 and trkA-positive dorsal root ganglion
neurons innervating the mouse lung,” Respiratory Physiology
and Neurobiology, vol. 144, no. 1, pp. 15–24, 2004.
[54] J. J. Brokaw and G. W. White, “Calcitonin gene-related peptide
potentiates substance P-induced plasma extravasation in the rat
trachea,” Lung, vol. 170, no. 2, pp. 85–93, 1992.
[55] J.-J. Xin, Y.-S. Su, Z.-K. Yang et al., “Effects of electroacupunc-
ture and regional thermal stimulation at ‘Zusanli’ (ST 36)
on pain thresholds of TRPV 1 knock-out mice,” Acupuncture
Research, vol. 37, no. 6, pp. 431–439, 2012.
[56] W.-S. Shim, M.-H. Tak, M.-H. Lee et al., “TRPV1 mediates
histamine-induced itching via the activation of phospholipase
A2 and 12-lipoxygenase,” The Journal of Neuroscience, vol. 27, no.
9, pp. 2331–2337, 2007.
[57] R.-X. Zhang, B. Liu, J.-T. Qiao et al., “Electroacupuncture
suppresses spinal expression of neurokinin-1 receptors induced
by persistent inflammation in rats,” Neuroscience Letters, vol.
384, no. 3, pp. 339–343, 2005.
[58] K. J. Tracey, “Physiology and immunology of the cholinergic
antiinflammatory pathway,” The Journal of Clinical Investigation,
vol. 117, no. 2, pp. 289–296, 2007.
[59] R. Torres-Rosas, G. Yehia, G. Peña et al., “Dopamine mediates
vagal modulation of the immune system by electroacupunc-
ture,” Nature Medicine, vol. 20, no. 3, pp. 291–295, 2014.
[60] N. Goldman, M. Chen, T. Fujita et al., “Adenosine A1 receptors
mediate local anti-nociceptive effects of acupuncture,” Nature
Neuroscience, vol. 13, no. 7, pp. 883–888, 2010.
[61] T. Takano, X. Chen, F. Luo et al., “Traditional acupuncture
triggers a local increase in adenosine in human subjects,”
Journal of Pain, vol. 13, no. 12, pp. 1215–1223, 2012.
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